Tiny gene mutations, each individually rare, pose more risk for
autism than had been previously thought, suggests a study funded
in part by the National Institute of Mental Health, a component
of the National Institutes of Health.

These spontaneous deletions and duplications of genetic material
were found to be ten times more prevalent in sporadic cases of
autism spectrum disorders (http://www.nimh.nih.gov/healthinformation/autismmenu.cfm)
than in healthy control subjects — but only twice as prevalent
in autism cases from families with more than one affected member.
The results implicate the anomalies as primary, rather than just
contributory, causes of the disorder in most cases when they are
present, according to the researchers. Although they might share
similar symptoms, different cases of autism could thus be traceable
to any of 100 or more genes, alone or in combination.

“These structural variations are emerging as a different kind
of genetic risk for autism than the more common sequence changes
in letters of the genetic code that we’ve been looking for,” explained
NIMH director Thomas Insel, M.D. “The best evidence yet that such
deletions and duplications are linked to the disorder, these findings
certainly complicate the search for genes contributing to autism.
These are rare changes, dispersed across the genome, and they tell
us that autism may be the final common path for many different
genetic abnormalities.”

“Our results show conclusively that these tiny glitches are frequent
in autism, occurring in at least ten percent of cases, and primarily
in the sporadic form of the disease, which accounts for 90 percent
of affected individuals,” added Sebat. “Understanding such sporadic
autism will require different genetic approaches and stepped-up
recruitment of families in which only one individual has the disease.”

Sebat and colleagues used new high resolution array technology
to detect mutations that were present in a child but not in either
parent. They screened genetic material from 264 families drawn,
in part, from the Autism Genetic Resource Exchange (AGRE) and the
NIMH Center for Collaborative Genetic Studies of Mental Disorders.

They found the spontaneous mutations in 14 of 195 people with
autism spectrum disorders compared to two of 196 unaffected individuals.
Among the 14 autism patients with mutations, 12 were the only affected
members of their family, while two were in families with other
affected individuals.

Since the rate of mutations was much lower in families with more
than one affected member, the researchers propose that “two different
genetic mechanisms contribute to risk: spontaneous mutation and
inheritance, with the latter being more frequent in families that
have multiple affected children.”

The two mutations detected in 196 healthy controls were duplications,
while 12 of those in people with autism were deletions of genetic
material. Relatively more females had the mutations, suggesting
that the anomalies may contribute to disease more equally across
the sexes than other causes of autism. Boys with autism outnumber
girls 4 to 1.

Since each mutation is individually rare — few were seen
more than once — the results suggest that many different
sites in the genome likely contribute to autism. “Failure to develop
social skills and repetitive and obsessive behavior may in fact
be the consequence of a reaction to many different cognitive impairments,” note
the researchers.

The new study is part of a growing body of NIH-funded research
on autism genetics. For example, researchers last fall reported
discovery of a gene version linked to autism and how it likely
works at the molecular level to increase risk (http://www.nih.gov/news/pr/oct2006/nimh-17.htm.)
The new study was also supported by the Simons Foundation, Autism
Speaks, Cure Autism Now, Southwestern Autism Research and Resource
Center, NAAR, Tampere University Hospital Medical Fund.

The National Institute of Mental Health (NIMH) (www.nimh.nih.gov/)
mission is to reduce the burden of mental and behavioral disorders
through research on mind, brain, and behavior.

The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.